1. Fuerst, Mark L.

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NEW YORK-A HER2 cancer vaccine shows clinical benefit in more than half of evaluable patients in an early clinical trial. Treatment with a HER2-targeted therapeutic cancer vaccine provided clinical benefit to patients with metastatic HER2-positive cancers who had not previously been treated with a HER2-targeted therapeutic, according to a new study.

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"We have translated a cancer vaccine from mice to human clinical trials with very promising early results, and intend to combine this vaccine with checkpoint inhibitors, as vaccines can induce T-cell responses that turn 'cold' tumors into 'hot' ones amenable to checkpoint blockade immunotherapy," said lead author Jay A. Berzofsky, MD, PhD, Chief of the Vaccine Branch at the Center for Cancer Research, NCI. He presented data from the phase I clinical trial at the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival.


HER2 Research

Previously, the researchers had developed and tested in mice and human patients a therapeutic cancer vaccine targeting HER2-expressing cancers comprising autologous dendritic cells transduced with an adenovirus expressing the non-signaling extracellular and transmembrane domains of HER2. HER2 is a driver oncogene in many cancers, including breast, ovarian, lung, colorectal, gastroesophageal, bladder, and others, Berzofsky noted.


In mice, the homologous vaccine cured virtually all mice with large established tumors up to 2 cm and with established macroscopic lung metastases, and the protection was dependent on antibodies to HER2 that inhibited HER2 phosphorylation but was FcR-independent antibody-mediated cellular cytotoxicity. This was distinct from the main recognized mechanism of the clinically approved anti-HER2 monoclonal antibody trastuzumab.


"We are carrying out a phase I clinical trial in patients with advanced metastatic cancers who had progressed on treatment with at least one line of standard therapy," said Berzofsky. Part 1 of the trial was carried out in patients naive to trastuzumab or other HER2-directed therapies to be able to demonstrate safety in the absence of complicating effects of prior HER2-targeted therapies.


Among 11 evaluable patients who had received more than the lowest dose of the vaccine, six (54%) had clinical benefit. One patient with ovarian cancer had a complete response that lasted 89 weeks, one patient with gastroesophageal cancer had a partial response that lasted 16 weeks, and four patients (two with colon cancer, one with prostate cancer, and one with ovarian cancer) had stable disease.


"Immunotherapy marshals the exquisite specificity of the immune system to destroy cancer, and some types may have potentially fewer side effects than traditional chemotherapy," said Berzofsky. "We are using a vaccine approach to generate an immune response to HER2, which is found at high levels on and drives the growth of several types of cancer, including breast, ovarian, lung, colorectal, and gastroesophageal cancers.


"Our results suggest that we have a very promising vaccine for HER2-overexpressing cancers," he continued. "We hope that one day the vaccine will provide a new treatment option for patients with these cancers." Early results in Part 2 of the study already showed two patients with stable disease.


The patients' vaccines are individually customized by Berzofsky and colleagues using their own immune cells isolated from their blood. The blood-derived immune cells are modified in several ways in the laboratory. The final product is administered intradermally and comprises patient-derived dendritic cells genetically modified with an adenovirus to produce parts of the HER2 protein.


In the dose-escalation portion of the phase I clinical trial, patients were injected with the vaccine on weeks 0, 4, 8, 16, and 24 after enrollment. Among the six patients who received the lowest dose of the vaccine, 5 million dendritic cells per injection, no clinical benefit was seen. Among the 11 patients who received either 10 million or 20 million dendritic cells per injection, six had clinical benefit.


Adverse reactions were predominantly injection-site reactions that did not require treatment. There was no evidence of cardiotoxicity.


"Based on the current safety and clinical benefit data, the dose of the vaccine was increased to 40 million dendritic cells per injection and the trial opened to patients who have previously been treated with a HER2-targeted therapeutic, including patients with breast cancer," noted Berzofsky. "Moving forward, we would like to investigate whether we can increase the proportion of people who benefit from treatment with the vaccine by combining it with checkpoint inhibitor therapy."


According to Berzofsky, the main scientific limitation of the study is that it is a relatively small, phase I clinical trial with no placebo control. However, the approach is sufficiently promising to warrant additional trials, he said.


Mark L. Fuerst is a contributing writer.